Selective acylation of secondary hydroxyl groups

Abstract

The invention provides methods and compositions for selectively acylating a specific hydroxyl group in a molecule of interest containing at least two unprotected secondary hydroxyl groups. Although the methods and compositions of the invention have general applicability, they are particularly useful in the selective acylation of taxane molecules.

1. A method of selectively acylating a taxane molecule, the method comprising the steps of
 (a) providing a solution of tetrahydrofuran and a taxane molecule having the formula: 
 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen; 
         R 2  is a benzoyl group; 
         R 4  is an acetate group; 
         R 7  is hydrogen; 
         R 10  is hydrogen or an acetate group; and 
         Rx is N═CHRc or —NHC(O)R n  , wherein Rc is an alkyl group, an aryl group, an arylalkyl group, an vinyl group, or an ether group; and R n  is an alkyl group, an aryl group, an arylalkyl group, a vinyl group, or an ether group; and 
         (b) contacting the solution with a hindered base and an acylating agent thereby to selectively acylate the hydroxyl group located at the C-2′ position, 
         wherein the hindered base is selected from the group consisting of pyridine derivatives substituted at least at the 2-position, N,N-diisopropylisobutylamine, N-ethyldicyclohexylamine, triethylmntine, trilsopropylanilne, tripropylamine, iniidazole, 1,5-diazabicylo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicylo[5.4.0]undec-7-ene. 
       
     
     
       2. The method of  claim 1 , wherein the acylating agent is an acid halide. 
     
     
       3. The method of  claim 2 , wherein the acid halide is an acid chloride. 
     
     
       4. The method of  claim 2 , wherein the acid halide is selected from the group consisting of benzoyl halide, tigloyl halide, hexanoyl halide, butyryl halide, 2 -methylbutyryl halide, phenylacetyl halide, furoyl balide, and tert-butyl halofonnate. 
     
     
       5. The method of  claim 1 , wherein the hindered base is a pyiidine derivative substituted at least at the 2-position. 
     
     
       6. The method of  claim 4 , wherein the hindered base is N-ethyldicyclohexylanune. 
     
     
       7. The method of  claim 1 , wherein the hindered base is selected from the group consisting of 2,6-lutidine and 2,4,6-collidine. 
     
     
       8. The method of  claim 1  further comprising the step of crystallizing the acylated compound with at least one solubilizing solvent and optionally at least one antisolvent. 
     
     
       9. The method of  claim 8 , wherein the at least one solubilizing solvent is a halogenated hydrocarbon. 
     
     
       10. The method of  claim 8 , wherein the solubilizing solvent is selected form the group consisting of acetone, methyl tert butyl ether, trifluorotoluene, or THF. 
     
     
       11. The method of  claim 8 , wherein the solubilizing solvent is methylene chloride. 
     
     
       12. The method of  claim 8 , wherein the at least one solubilizing solvent is methylene chloride and the antisolvent is hexane. 
     
     
       13. The method of  claim 8 , wherein the antisolvent is a hydrocarbon alkane. 
     
     
       14. The method of  claim 1  wherein R 10  is hydrogen. 
     
     
       15. The method of  claim 1  wherein R 10  is an acetate group. 
     
     
       16. The method of  claim 14  wherein Rx is N═CHRc, and Rc is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl; 2furanyl, and tert-butoxy. 
     
     
       17. The method of  claim 14  wherein Rx is —NHC(O)R n , and R n  is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl, 2-Ibranyl, and tert-butoxy. 
     
     
       18. The method of  claim 15  wherein Rx is N═CHR, and R is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl, 2-furanyl, and tert-butoxy. 
     
     
       19. The method of  claim 15  wherein Rx is —NHC(O)R n , and R n  is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, beniyl, 2-furmnyl, and tert-butoxy. 
     
     
       20. A method of selectively acylating a taxane molecule, the method comprising the steps of
 (a) providing a solution of tetrahydrofuran and a taxane molecule having the formula: 
 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen; 
         R 2  is a benzoyl group; 
         R 4  is an acetate group; 
         R 7  is hydrogen; 
         R 10  is hydrogen or an acetate group; and 
         Rx is N═CHRc or —NHC(O)R n , wherein Rc is an alkyl group, an aryl group, an arylalkyl group, an vinyl group, or an ether group; and R n  is an alkyl group, an aryl group, an arylalkyl group, a vinyl group, or an ether group; and 
         (b) adding 2,6-lutidine or N ethyldicyclohexylaniine and an acid chloride to the solution thereby to selectively acylate the hydroxyl group located at the C-2′ position. 
       
     
     
       21. The method of  claim 20  wherein R 10  is hydrogen. 
     
     
       22. The method of  claim 20  wherein R 10  is an acetate group. 
     
     
       23. The method of  claim 21  wherein Rx is N═CHRc, and Rc is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl; 2furanyl, and tert-butoxy. 
     
     
       24. The method of  claim 21  wherein Rx is —NHC(O)R n , and R n  is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl, 2-furanyl, and tert(-butoxy. 
     
     
       25. The method of  claim 22  wherein Rx is N═CHR, and R is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, beuzyl, 2furanyl, and tert-butoxy. 
     
     
       26. The method of  claim 22  wherein Rx is —NHC(O)R n , and R n  is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl, 2-furanly, and tert-butoxy. 
     
     
       27. The method of  claim 23  wherein the acid chloride is selected from the group consisting of benzoyl chloride, tigloyl chloride, hexanoyl chloride, butyryl chloride, 2-methylbutyryl chloride, phenylacetyl chloride, furoyl chloride, and tert butyl chioroformate. 
     
     
       28. The method of  claim 24  wherein the acid chloride is selected from the group consisting of berazoyl chloride, tigloyl chloride, hexanoyl chloride, butyryl chloride, 2-methylbutyryl chloride, phenylacetyl chloride, furoyl chloride, and tert-butyl chloroformate. 
     
     
       29. The method of  claim 25  wherein the acid chloride is selected from the group consisting of berazoyl chloride, tigloyl chloride, hexanoyl chloride, butyryl chloride, 2-methylbutyryl chloride, phenylacetyl chloride, furoyl chloride, and tert-butyl chloroformate. 
     
     
       30. The method of  claim 26  wherein the acid chloride is selected from the group consisting of benzoyl chloride, tigloyl chloride, hexanoyl chloride, butyryl chloride, 2-methylbutyryl chloride, phenylacetyl chloride, furoyl chloride, and tert-butyl chioroformnate. 
     
     
       31. The method of  claim 20  wherein R 10  is an acetate group, Rx is —NHC(O)R n , wherein R n  is phenyl, and the acid chloride is benzoyl chloride. 
     
     
       32. The method of  claim 20  wherein R 10  is an acetate group, Rx is —NHC(O)R n , wherein R n  is 1-methyl-1-propenyl, and the acid chloride is benzoyl chloride. 
     
     
       33. The method of  claim 20  wherein R 10  is an acetate group, Rx is —NHC(O)R n , wherein R n  is n-pentyl, and the acid chloride is benzoyl chloride. 
     
     
       34. The method of  claim 20  further comprising the step of crystallizing the acylated compound with at least one solubilizing solvent and optionally at least one antisolvent. 
     
     
       35. The method of  claim 34 , wherein the at least one solubilizing solvent is a halogenated hydrocarbon. 
     
     
       36. The method of  claim 34 , wherein the solubilizing solvent is selected form the group consisting of acetone, methyl tert butyl ether, trifluorotoluene, or THF. 
     
     
       37. The method of  claim 34 , wherein the solubilizing solvent is methylene chloride. 
     
     
       38. The method of  claim 34 , wherein the at least one solubilizing solvent is methylene chloride and the antisolvent is hexane. 
     
     
       39. The method of  claim 34 , wherein the antisolvent is a hydrocarbon alkane. 
     
     
       40. The method of  claim 1 , wherein the method results in at least about 95% of an ending taxane acylated at the C-2′ position and less than about 0.1% of the starting texans remains unreacted after the contacting step. 
     
     
       41. The method of  claim 40 , wherein the method results in at least about 99% of an ending taxane acylated at the C-2′ position. 
     
     
       42. The method of  claim 20 , wherein the method results in at least about 95% of an ending taxane acylated at the C-2′ position and less than about 0.1% of the starting taxane remains unreacted after the contacting step. 
     
     
       43. The method of  claim 42 , wherein the method results in at least about 99% of an ending taxane acylated at the C-2′ position.